As a physician-scientist my goal is to identify the causes of diseases, to better understand pathogenesis and provide improved clinical care to patients. My research group focuses on integrating human genetics with mechanistic studies to better understand disease processes. I have worked to identify the genetic causes of autoinflammatory diseases, or diseases of activation of the innate immune system, and used this as a starting point for understanding disease pathogenesis. This work has identification of VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome and autoinflammatory disease with severe rheumatic and hematologic symptoms. Although only recently identified, VEXAS syndrome is one of the most common autoinflammatory diseases and current treatments are largely ineffective. My goal as a physician scientist is to study disease mechanisms in the laboratory, and to use these insights directly to help improve clinical care.
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a disease caused by acquired mutations in the gene UBA1 that leads to autoimmunity and blood issues. VEXAS syndrome can have variable symptoms, is severe with increased mortality, and does not respond to common medications. We have shown that loss of the UBA1 protein in cell lines in the laboratory, leads to inflammation, however these systems have not been able to demonstrate autoimmunity seen in patients. To better understand why UBA1 mutations lead to autoimmunity and how best to treat this disease, we have generated and characterized genetic mouse models, that provides us with unique tools to understand the role of UBA1 in multiorgan disease. We have already shown that Uba1 knockout or deletion leads systemic inflammation, however we have yet to analyze our mouse model for autoimmune manifestations, present in VEXAS syndrome patients. We will use these models to determine the role of UBA1 in autoimmune disease, through detailed phenotyping for arthritis, skin, lung and cartilage inflammation. We will determine which types of blood cells lead to inflammation in VEXAS models and the potential contribution of UBA1 more broadly to lupus and inflammatory arthritis. Our work will reveal not only how UBA1 mutations lead to autoimmune disease, but also the role of UBA1 in common rheumatic diseases, and may have broad implications for understanding and treating such diseases.